1. Field of the Invention
The present invention relates to stable and active complexes of adenosine, adenosine monophosphate and adenosine triphosphate with aminoalcohols, alkylamino-alkanols, dialkylamino-alkanols, and their salts for treating cardiovascular and neurological and other diseases including, but not limited to, pulmonary artery hypertension, cardiac failure and cerebral vasospasm.
2. Description of the Prior Art
1. Adenosine
Adenosine is a ubiquitous purine that is a modulator of numerous physiological activities, particularly within the cardiovascular and nervous systems. Adenosine has a variety of extracellular and intracellular effects. The effects of adenosine appear to be mediated by specific cell surface receptor proteins (A1, A2a, A2b, and A3). Adenosine modulates diverse physiological functions including, arterial vasodilation, reduction of cardiac rate, down regulation of several brain activities, inhibition of acute inflammation, stimulation of gluconeogenesis, and inhibition of lipolysis. Adenylate cyclase mediates many of adenosine's effects, e.g., the opening of potassium channels and the reduction of flux through calcium channels.
1.1 Adenosine is a potent arterial vasodilator.
Adenosine constantly modulates vascular tone, significantly under ischemic conditions, thus contributing to the protection of a large number of tissues (heart, brain, liver, kidney, stomach, etc.). Currently, adenosine vasodilating properties are used for ischemic heart disease diagnosis (e.g., as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately) and occasionally for cardioprotection during revascularization procedures.                Acting via A2 receptors adenosine increases cyclic AMP which promotes vasodilatation by both decreasing intracellular calcium and directly inhibiting myosin light chain kinase phosphorylation.        Adenosine has a preferential vasodilator effect on the pulmonary circulation in human. Morgan J M—Adenosine as a vasodilator in primary pulmonary hypertension. Circulation. 1991 September; 84(3):1145-9. This effect is confined to the pulmonary arterial tissues for dosages in the 50 μg/kg/mn range given in perfusion for 15 minutes. Fullerton D A—Adenosine effectively controls pulmonary hypertension after cardiac operations—Ann Thorac Surg. 1996 April; 61(4):1118-23. At dosages of 140 μg/kg/mn for 6 mn (Adenoscan prescribing information) a systemic vasodilating effect is observed and hypotension can be seen in 2% of patients. Due to its very short half-life, less than 5 seconds, usage of adenosine is currently limited to IV acute testing in order to determine those patients who may respond to calcium channel blockers or other vasodilating therapies prescribed in pulmonary artery hypertension.        Adenosine induces collateral circulation via inducing growth factors and triggering ischemic preconditioning, both of which induce ischemic tolerance in advance. Adenosine is also known to reduce the release of noradrenaline, production of endothelin, and attenuate the activation of renin-angiotensin system, all of which are believed to cause cardiac hypertrophy and remodelling. Exogenous adenosine is further known to reduce the severity of ischemia and reperfusion injury. Finally, adenosine is reported to counteract neurohumoral factors, i.e., cytokine systems, known to be related to the pathophysiology of cardiac failure. Kitakaze M, Hori M—Adenosine therapy: a new approach to chronic heart failure. Expert Opin Investig Drugs 2000 November; 9(11):2519-35.        Intra-arterial (133)Xe cerebral blood flow (CBF) measurements suggest that intracarotid adenosine, in a dose that lacks significant systemic side effects, profoundly increases CBF, whereas nitroprusside has no effect. Joshi S et al—In nonhuman primates intracarotid adenosine, but not sodium nitroprusside, increases cerebral blood flow. Anesth Analg. 2002 February; 94(2):393-9.        In the heart, adenosine has been shown to suppress pacemaker activity and slow atrio-ventricular conduction. It is currently used by intravenous bolus administration to treat supraventricular tachycardia.1.2 Adenosine is a neuromediator.        
In most brain areas, high extracellular adenosine concentrations, through A1 and A2 adenosine receptors, decrease neuronal activity. See Dunwiddie T V, Masino S A., Neuroscience 2001, 107(4):653-63. See also, The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci. 2001; 24:31-55.                Adenosine is also thought to play a key role in the induction of sleep. Investigations into the relationship between adenosine and sleep surged following the discovery that caffeine's stimulating characteristics stem from its ability to prevent adenosine from binding to cells and launching distinct actions. Now a large body of work has revealed the details of how, under normal circumstances, adenosine promotes sleep. Many studies in animals have shown that blocking adenosine's actions in the brain increases alertness, while injections of adenosine or similar compounds induce apparently normal sleep. See Porkka-Heiskanen T., et al., Adenosine: A mediator of the sleep-inducing effects of prolonged wakefulness. Science 276 (May 23):1265, 1997.        Adenosine also participates in many local regulatory mechanisms, such as those occurring in synapses, in the central nervous system (CNS) and at neuroeffector junctions in the peripheral nervous system. In the CNS, adenosine is known to inhibit the release of a variety of neurotransmitters, such as noradrenaline, dopamine, serotonin, glutamate and GABA, to depress neurotransmission, to reduce neuronal firing, to induce spinal analgesia, and to possess anxiolytic properties.        Adenosine can also function as an inhibitory modulator of seizure activity, of particular importance in epilepsy and convulsions of the alcohol withdrawal syndrome. For review, see Ph. De Witte, E. Pinto, M Ansseau and P. Verbanck. Alcohol and withdrawal: from animal research to clinical issues, Neuroscience & Biobehavioral Reviews, 2003;27:189-197. This likely represents an adaptive response to seizure severity induced by repeated episodes of withdrawal.        The identification of adenosine as a transactivator or the Trk tyrosine kinase receptor suggests that it can replace neurotrophins as a potential treatment for a wide range of neurological disorders, including Alzheimer disease, cerebral ischemia, hyperalgesia, and Parkinson's disease. See Lee F S, Rajagopal R, Chao M V Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev. 2002 February 13(1):11-7. Indeed, adenosine activates the Trk receptor tyrosine kinase and mediates neuronal cell survival in the absence of neurotrophins. Adenosine also offsets impaired cholinergic signalling. The regulation of the cholinergic calcium signalling in astroglial cells is thought to play a crucial role in the pathogenesis of Alzheimer's disease. Various study results suggest that impaired cholinergic signalling, the cardinal symptom of Alzheimer's disease, can be reinforced at the second messenger level by an alternative intracellular Ca(2+) mobilizing path, which can be brought into play by the concomitant activation of A1 purinoceptors. See Ferroni S, Marchini C, Ogata T. Schubert P., J Neurosci Res. 2002 June 1;68(5):615-21, Recovery of deficient cholinergic calcium signalling by adenosine in cultured rat cortical astrocytes. Therefore, it is thought that adenosine can stop and prevent neurons from calcium dysregulation.1.3 Adenosine has anti-inflammatory properties.        
Adenosine signalling strongly affects inflammatory cell function. (Ohta, A. & Sitkovsky, M Role of G-protein-coupled receptors in downregulation of inflammation and protection from tissue damage. Nature 414, 916-920 (2001)) thus resulting in:                Inhibition of leucocytes migration and free radical production. Cronstein B N. Adenosine, an endogenous anti-inflammatory agent, J Appl Physiol 1994 January; 76(1):5-13.        Down-regulation of pro-inflammatory cytokines such as TNF-alpha, IL-6, IFN-gamma, IL-12, and the up-regulation of the anti-inflammatory cytokine IL-10. Zdenek Zidek .Adenosine cyclic AMP pathways and cytokine expression—Review—European Cytokine Network. Vol. 10, Issue 3, September 1999: 319-28.        A2 receptor stimulation also inhibits NFkappaB activity, whereas activation of other adenosine receptors have no effect (activation of NFkappaB induces gene programs leading to transcription of factors that promote inflammation, such as leukocyte adhesion molecules, cytokines, and chemokines).        
Despite its role in multiple biological functions and pharmacological processes, the very short plasmatic half-life of adenosine (less than 5 sec.) restricts its therapeutic use to massive bolus injections by the intravenous route for treating supraventricular tachycardia with the risk of serious A1 related adverse-effects such as chest-pain, AV block, and bronchoconstriction.
2. AMP
The purine nucleotide AMP is a natural “adenosine precursor” which ultimately converts into adenosine by ecto-5′-nucleotidase on the extra-cellular surface of all cells. Ecto-5′-nucleotidase is a ubiquitous wide spread enzyme that hydrolyzes a variety of nucleotides, but has greatest affinity for AMP that it efficiently converts to adenosine. The vasodilating effects of AMP are mentioned in the Monographs of Commercialized AMP Products Cardiomone and Adenyl. 
3. ATP
ATP is a naturally occurring nucleotide which is present in every cell. Extracellular ATP appears to be involved in the regulation of a variety of biological processes via P2 receptors divided into P2X ligand-gated ion channel and P2Y G-protein-coupled receptors families.
3.1 ATP potentiates cytostatic agents.
                In in vitro and in vivo animal studies, ATP has been shown to inhibit the growth of several solid carcinoma tumours (colon, pancreas, esophagus) and of several cancer cell lines (prostate, breast, melanoma, myeloid cells). See Agteresch H J & al, Adenosine Triphosphate. Established and potential clinical applications. Drugs 1999 August; 58(2):211-232. The underlying predominant mechanism is not clear but increased membrane permeability (not observed in untransformed cells) seems predominant. Potentiation effects of cytostatic agents were also observed in several in vitro and animal studies (melanoma, ovarian carcinoma) and some human studies (myeloid leukaemia, glioma).        ATP infusion in patients with advanced cancer is feasible but is limited by dyspnoea and chest tightness. A Phase II trial in patients with non-small cell lung cancer showed that it reduces or inhibits weight loss. See Haskell C M & al., Phase I trial of extracellular ATP in patients with advanced cancer. Med Pediatr Oncol 1996; 27(3):165-73. This effect has also been observed in mice with human pancreatic carcinoma.        Cachexia is caused by elevated lipolysis, protein breakdown and gluconeogenesis. It is also correlated with lower ATP levels. It was suggested that the administration of extracellular ATP inhibits Cori cycle (i.e. the gluconeogenesis from lactate followed by reconversion of glucose to lactate in peripheral tissue), activity which is a potential means of inhibiting weight loss.3.2 ATP is the universal source of cell energy.        
ATP is depleted during exercise, in chronic fatigue syndrome and in heart failure. See Steele D S, Duke A M. Metabolic factors contributing to altered Ca2+ regulation in skeletal muscle fatigue Acta Physiol Scand. 2003 September; 179(1):39-48/Harmer A R & al-Skeletal muscle metabolic and ionic adaptations during intense exercise following sprint training in humans J Appl Physiol. 2000 November; 89(5):1793-803/Forsyth L M. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999 February; 82(2):185-91/Ventura-Clapier R. Metabolic myopathy in heart failure. News Physiol Sci. 2002 October; 17:191-6/Energy metabolism in heart failure. Physiol. 2004 February 15;555(Pt 1):1-13. Epub 2003 Dec. 05.
3.3 ATP is a potent vasodilating agent.
ATP exerts its vasodilating effects mainly through P2Y receptors and ATP-sensitive potassium channel openers. Van Aken H et al-Haemodynamic and cerebral effects of ATP-induced hypotension. Br J Anaesth. 1984 December; 56(12):1409-16.
Despite possessing numerous and very important physiological and pharmacological activities, adenosine and adenosine triphosphate (ATP) have both a very short plasma half-life (less than 5 seconds) and therefore cannot be used orally. Although having a longer half life, adenosine monophosphate (AMP) has a poor gastrointestinal bioavailability which restricts its medical applications. Further, when administered intravenously, the effects of adenosine and ATP are limited in duration (e.g. less than one minute after adenosine bolus injection). Thus, there is a need for improved compositions and methods which take advantage of the pharmacological effects of adenosine and adenosine phosphates while having improved stability when administered orally (as well as intravenously).
Given that adenosine and adenosine phosphates possess numerous physiological and pharmacological activities significant research has been devoted in the pursuit of harnessing their pharmacological effects in therapeutic compositions and methods. For example, U.S. Pat. No. 3,993,639 (the '639 patent) describes heptaminol adenosine-5′-monophosphate. This compound has interesting properties in the cardiovascular domain, particularly in the treatment of venous vascular insufficiencies (phlebology). However the '639 patent document does not teach nor suggest the formation of complexes between adenosine and tertiary amines such as dialkylaminoalkanols nor pharmaceutical compositions between adenosine monophosphate and tertiary amines as dialkylaminoalkanols nor that primary amine heptaminol might improve adenosine-5′-monophosphate bioavailability. Thus, no properties of such complexes, e.g. enhanced capacity to cross the gastrointestinal barrier, are described or suggested.
The present invention provides compositions and method which permit the oral use of adenosine and adenosine phosphates for cardiovascular applications such as pulmonary artery hypertension, cardiac failure and other diseases. The invention also enhances AMP gastrointestinal bioavailability and efficacy. The invention further permits prolonged activity of those substances when administered intravenously. In addition, the invention contemplates method of treating several human (as well as animal) cardiovascular and neurological medical conditions that could be improved by an effective amount of adenosine, ATP or AMP combined with dialkylaminoalcohols and their salts.